Dr McCann on the Increasing Use of TKIs for HER2+ Breast Cancer Brain Metastases

"One of the big challenges in treating patients with HER2-positive breast cancer is that they can develop brain metastases later on [in the disease course]. This is challenging because we don’t have a lot of therapies that cross the blood-brain barrier. The efficacy of TKIs…has really revolutionized how we treat our patients with brain metastases."

Kelly E. McCann, MD, PhD, a breast medical oncologist and an assistant clinical professor of medicine at the UCLA Health David Geffen School of Medicine, discussed the increasing use of drug classes beyond chemotherapy and antibody-drug conjugates (ADCs) for the treatment of patients with HER2-positive breast cancer, particularly those with brain metastases.

In addition to chemotherapy and ADCs, TKIs have played an increasingly significant role in the management of HER2-positive breast cancer, particularly in patients with brain metastases, McCann began. One of the primary challenges in managing HER2-positive disease is the development of central nervous system (CNS) metastases, as many systemic therapies have limited ability to cross the blood-brain barrier (BBB), she explained.

HER2-targeted TKIs, including neratinib (Nerlynx) and tucatinib (Tukysa), have demonstrated efficacy in addressing this unmet need, McCann continued. Although neratinib is a pan-HER inhibitor, the phase 2 HER2CLIMB trial (NCT02614794) uniquely evaluated tucatinib in a population where 47.5% of enrolled patients had known brain metastases—a group often excluded from clinical trials, she reported.

The results of HER2CLIMB have helped to establish tucatinib in combination with capecitabine as a key treatment option for patients with HER2-positive breast cancer and CNS involvement, McCann said. Emerging data suggest that fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) may also have activity in brain metastases, despite ADCs traditionally being thought to have limited CNS penetration, she noted. This effect may be attributed to payload diffusion, where the cytotoxic agent released intracellularly can cross the BBB and exert therapeutic activity in the CNS, she explained. As research continues, TKIs and ADCs are expected to further refine the treatment paradigm for patients with HER2-positive breast cancer and brain metastases, McCann concluded.